Integrin control of the transforming growth factor-β pathway in glioblastoma

Transforming growth factor-β is a central mediator of the malignant phenotype of glioblastoma, the most common and malignant form of intrinsic brain tumours. Transforming growth factor-β promotes invasiveness and angiogenesis, maintains cancer cell stemness and induces profound immunosuppression in the host. Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation, differentiation and motility, and may be involved in the activation of transforming growth factor-β. We report that αvβ3, αvβ5 and αvβ8 integrins are broadly expressed not only in glioblastoma blood vessels but also in tumour cells. Exposure to αv, β3 or β5 neutralizing antibodies, RNA interference-mediated integrin gene silencing or pharmacological integrin inhibition using the cyclic RGD peptide EMD 121974 (cilengitide) results in reduced phosphorylation of Smad2 in most glioma cell lines, including glioma-initiating cell lines and reduced transforming growth factor-β-mediated reporter gene activity, coinciding with reduced transforming growth factor-β protein levels in the supernatant. Time course experiments indicated that the loss of transforming growth factor-β bioactivity due to integrin inhibition likely results from two distinct mechanisms: an early effect on activation of preformed inactive protein, and second, major effect on transforming growth factor-β gene transcription as confirmed by decreased activity of the transforming growth factor-β gene promoter and decreased transforming growth factor-β1 and transforming growth factor-β2 messenger RNA expression levels. In vivo, EMD 121974 (cilengitide), which is currently in late clinical development as an antiangiogenic agent in newly diagnosed glioblastoma, was a weak antagonist of pSmad2 phosphorylation. These results validate integrin inhibition as a promising strategy not only to inhibit angiogenesis, but also to block transforming growth factor-β-controlled features of malignancy including invasiveness, stemness and immunosuppression in human glioblastom

The functional genome of CA1 and CA3 neurons under native conditions and in response to ischemia

<p>Abstract</p> <p>Background</p> <p>The different physiological repertoire of CA3 and CA1 neurons in the hippocampus, as well as their differing behaviour after noxious stimuli are ultimately based upon differences in the expressed genome. We have compared CA3 and CA1 gene expression in the uninjured brain, and after cerebral ischemia using laser microdissection (LMD), RNA amplification, and array hybridization.</p> <p>Results</p> <p>Profiling in CA1 vs. CA3 under normoxic conditions detected more than 1000 differentially expressed genes that belong to different, physiologically relevant gene ontology groups in both cell types. The comparison of each region under normoxic and ischemic conditions revealed more than 5000 ischemia-regulated genes for each individual cell type. Surprisingly, there was a high co-regulation in both regions. In the ischemic state, only about 100 genes were found to be differentially expressed in CA3 and CA1. The majority of these genes were also different in the native state. A minority of interesting genes (e.g. inhibinbetaA) displayed divergent expression preference under native and ischemic conditions with partially opposing directions of regulation in both cell types.</p> <p>Conclusion</p> <p>The differences found in two morphologically very similar cell types situated next to each other in the CNS are large providing a rational basis for physiological differences. Unexpectedly, the genomic response to ischemia is highly similar in these two neuron types, leading to a substantial attenuation of functional genomic differences in these two cell types. Also, the majority of changes that exist in the ischemic state are not generated de novo by the ischemic stimulus, but are preexistant from the genomic repertoire in the native situation. This unexpected influence of a strong noxious stimulus on cell-specific gene expression differences can be explained by the activation of a cell-type independent conserved gene-expression program. Our data generate both novel insights into the relation of the quiescent and stimulus-induced transcriptome in different cells, and provide a large dataset to the research community, both for mapping purposes, as well as for physiological and pathophysiological research.</p

European Registry of Cardiac Arrest – Study-THREE (EuReCa THREE) – an international, prospective, multi-centre, three-month survey of epidemiology, treatment and outcome of patients with out-of-hospital cardiac arrest in Europe – the study protocol

Background The aim of the European Registry of Cardiac Arrest (EuReCa) network is to provide high quality evidence on epidemiology of out-of-hospital cardiac arrest (OHCA) in Europe by supporting and developing cardiac arrest registries and performing European-wide studies. To date, the EuReCa ONE and EuReCa TWO studies have involved around 28 countries, with population covered increasing from the first to the second study. The aim of the EuReCa THREE study is to build on previous work and to support the promotion of quality data collection on OHCA throughout Europe. Methods/design EuReCa THREE will be the third prospective cohort study on epidemiology of OHCA and will involve around 30 European countries. The study will be conducted between 1st September and 30th November 2022. Data will be collected on cardiac arrest cases attended, resuscitation attempted, patient and cardiac arrest event characteristics and outcomes (including return of spontaneous circulation, status on hospital arrival and discharge). A particular focus for EuReCa THREE will be to describe key time intervals in OHCA management; time from call to EMS arrival on scene, time from cardiac arrest to start CPR, time from EMS arrival to delivery of patient to hospital. EuReCa THREE was registered with the German Registry of Clinical Trials Registration Number: DRKS00028591 searchable via WHO meta-registry (https://apps.who.int/trialsearch/). Discussion The EuReCa THREE study will increase our knowledge on longitudinal OHCA epidemiology and provide new knowledge on crucial time intervals in OHCA management in Europe. However, the primary aim of building a network to support quality data on OHCA, remains the central tenant of the EuReCa project

Reduced risk of myocardial infarct and revascularization following coronary artery bypass grafting compared with percutaneous coronary intervention in patients with chronic kidney disease

Coronary atherosclerotic disease is highly prevalent in chronic kidney disease (CKD). Although revascularization improves outcomes, procedural risks are increased in CKD and unbiased data comparing bypass surgery (CABG) and percutaneous intervention (PCI) in CKD are sparse. To compare outcomes of CABG and PCI in stage 3-5 CKD, we identified randomized trials comparing these procedures. Investigators were contacted to obtain individual, patient-level data. Ten of 27 trials meeting inclusion criteria provided data. These trials enrolled 3993 patients encompassing 526 patients with stage 3-5 CKD of which 137 were stage 3b-5 CKD. Among individuals with stage 3-5 CKD survival through 5-years was not different following CABG compared with PCI (hazard ratio 0.99, 95% confidence interval: 0.67, 1.46) or stage 3b-5 CKD (1.29: 0.68, 2.46). However, CKD modified the impact on survival free from myocardial infarction: it was not different between CABG and PCI for individuals with preserved kidney function (0.97: 0.80, 1.17), but was significantly lower following CABG in stage 3-5 CKD (0.49: 0.29, 0.82) and stage 3b-5 CKD (0.23: 0.09, 0.58). Repeat revascularization was reduced following CABG compared with PCI regardless of baseline kidney function. Results were limited by unavailability of data from several trials and paucity of enrolled patients with stage 4-5 CKD. Thus, our patient-level meta-analysis of individuals with CKD randomized to CABG versus PCI suggests that CABG significantly reduces the risk of subsequent myocardial infarction and revascularization without impacting survival in these patients

The HD(CP)² Observational Prototype Experiment (HOPE) – an overview

The HD(CP)2 Observational Prototype Experiment (HOPE) was performed as a major 2-month field experiment in Jülich, Germany, in April and May 2013, followed by a smaller campaign in Melpitz, Germany, in September 2013. HOPE has been designed to provide an observational dataset for a critical evaluation of the new German community atmospheric icosahedral non-hydrostatic (ICON) model at the scale of the model simulations and further to provide information on land-surface–atmospheric boundary layer exchange, cloud and precipitation processes, as well as sub-grid variability and microphysical properties that are subject to parameterizations. HOPE focuses on the onset of clouds and precipitation in the convective atmospheric boundary layer. This paper summarizes the instrument set-ups, the intensive observation periods, and example results from both campaigns. HOPE-Jülich instrumentation included a radio sounding station, 4 Doppler lidars, 4 Raman lidars (3 of them provide temperature, 3 of them water vapour, and all of them particle backscatter data), 1 water vapour differential absorption lidar, 3 cloud radars, 5 microwave radiometers, 3 rain radars, 6 sky imagers, 99 pyranometers, and 5 sun photometers operated at different sites, some of them in synergy. The HOPE-Melpitz campaign combined ground-based remote sensing of aerosols and clouds with helicopter- and balloon-based in situ observations in the atmospheric column and at the surface. HOPE provided an unprecedented collection of atmospheric dynamical, thermodynamical, and micro- and macrophysical properties of aerosols, clouds, and precipitation with high spatial and temporal resolution within a cube of approximately 10  ×  10  ×  10 km3. HOPE data will significantly contribute to our understanding of boundary layer dynamics and the formation of clouds and precipitation. The datasets have been made available through a dedicated data portal. First applications of HOPE data for model evaluation have shown a general agreement between observed and modelled boundary layer height, turbulence characteristics, and cloud coverage, but they also point to significant differences that deserve further investigations from both the observational and the modelling perspective

Sorafenib decreases proliferation and induces apoptosis of prostate cancer cells by inhibition of the androgen receptor and Akt signaling pathways

Antihormonal and chemotherapy are standard treatments for nonorgan-confined prostate cancer. The effectivity of these therapies is limited and the development of alternative approaches is necessary. In the present study, we report on the use of the multikinase inhibitor sorafenib in a panel of prostate cancer cell lines and their derivatives which mimic endocrine and chemotherapy resistance. 3H-thymidine incorporation assays revealed that sorafenib causes a dose-dependent inhibition of proliferation of all cell lines associated with downregulation of cyclin-dependent kinase 2 and cyclin D1 expression. Apoptosis was induced at 2 μM of sorafenib in androgen-sensitive cells, whereas a higher dose of the drug was needed in castration-resistant cell lines. Sorafenib stimulated apoptosis in prostate cancer cell lines through downregulation of myeloid cell leukemia-1 (MCL-1) expression and Akt phosphorylation. Although concentrations of sorafenib required for the antitumor effect in therapy-resistant sublines were higher than those needed in parental cells, the drug showed efficacy in cells which became resistant to bicalutamide and docetaxel respectively. Most interestingly, we show that sorafenib has an inhibitory effect on androgen receptor (AR) and prostate-specific antigen expression. In cells in which AR expression was downregulated by short interfering RNA, the treatment with sorafenib increased apoptosis in an additive manner. In summary, the results of the present study indicate that there is a potential to use sorafenib in prostate cancers as an adjuvant therapy option to current androgen ablation treatments, but also in progressed prostate cancers that become unresponsive to standard therapies

UCRAID (Ukrainian Citizen and refugee electronic support in Respiratory diseases, Allergy, Immunology and Dermatology) action plan.

Eight million Ukrainians have taken refuge in the European Union. Many have asthma and/or allergic rhinitis and/or urticaria, and around 100,000 may have a severe disease. Cultural and language barriers are a major obstacle to appropriate management. Two widely available mHealth apps, MASK-air® (Mobile Airways Sentinel NetworK) for the management of rhinitis and asthma and CRUSE® (Chronic Urticaria Self Evaluation) for patients with chronic spontaneous urticaria, were updated to include Ukrainian versions that make the documented information available to treating physicians in their own language. The Ukrainian patients fill in the questionnaires and daily symptom-medication scores for asthma, rhinitis (MASK-air) or urticaria (CRUSE) in Ukrainian. Then, following the GDPR, patients grant their physician access to the app by scanning a QR code displayed on the physician's computer enabling the physician to read the app contents in his/her own language. This service is available freely. It takes less than a minute to show patient data to the physician in the physician's web browser. UCRAID-developed by ARIA (Allergic Rhinitis and its Impact on Asthma) and UCARE (Urticaria Centers of Reference and Excellence)-is under the auspices of the Ukraine Ministry of Health as well as European (European Academy of Allergy and Clinical immunology, EAACI, European Respiratory Society, ERS, European Society of Dermatologic Research, ESDR) and national societies

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p <2.8 x 10(-6)) enrichment of associations at the gene level, forLOC388780(20p13; uncharacterized gene), and forVEPH1(3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (atp(T) = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase;p = 8 x 10(-13)), bipolar disorder (1.53[1.44; 1.63];p = 1 x 10(-43)), schizophrenia (1.36[1.28; 1.45];p = 4 x 10(-22)), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30];p = 3 x 10(-12)), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96];p = 5 x 10(-4)), educational attainment (0.86[0.82; 0.91];p = 2 x 10(-7)), and intelligence (0.72[0.68; 0.76];p = 9 x 10(-29)). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.Peer reviewe